A vanilloid receptor that is a benzoimidazole derivative according to the present invention has always been assumed to be a receptor of capsaicin (trans-8-methyl-N-vanilyl-6-noneneamide) which is the active component of chili peppers. By Caterina et al. in 1997, the above receptor was cloned, which is called the vanilloid receptor subtype 1 (hereinafter referred to as “VR-1”) (Caterina et al., Nature, 1997, 389, 816). VR-1 which is distributed in fine unmyelinated neurons (C-fibers) and thin myelinated neurons (A-fibers) in the human body is activated from external or internal stimuli so that cations such as calcium, sodium, etc., are intensively introduced into the terminals of nerve fibers, and is thus known to be an ion channel capable of responding to pain stimuli. The external stimuli that activate VR-1 are reported to include heat stimuli or noxious stimuli by acids, as well as vanilloid compounds (Tominaga et al., Neuron, 1998, 21, 531), and the internal stimuli are known to be leukotriene metabolites such as 12-hydroperoxyeicosatetraenoic acid (12-HPETE) (Hwang at al., PNAS, 2000, 97, 3655) and arachidonic acid derivatives such as anandamide (Premkumar et al., Nature, 2000, 408, 985).
Based on such physiological actions, VR-1 has received attention as an integrated regulator that plays an important role in transmitting a variety of external noxious stimuli into nerve cells in vivo. Recently, a knockout mouse from which VR-1 genes was removed was produced (Caterina et al., Science, 2000, 288, 306), and its pain reaction was not greatly different from that of a normal mouse with respect to general stimuli, but was considerably reduced with respect to heat stimuli, heat hyperalgesia, etc., thereby confirming the importance of VR-1 with respect to noxious stimuli.
VR-1 is mainly expressed in primary sensory neurons in vivo (Caterina et al., Nature, 1997, 389, 816), and these sensory neurons are essential to regulating functions of internal organs of the human body, including the skin, bone tissue, bladder, gastrointestinal tract, lung, etc. In addition, VR-1 is considered to be important in regulating cell division or cell signals while being distributed throughout the entire body or the other nerve cells including the central nervous system, kidney, stomach, or T-cells (Nozawa et al., Neuroscience Letter, 2001, 309, 33; Yiangou et al., Lancet (North America Edition), 2001, 357, 1338; Birder et al., PNAS, 2001, 98, 13396).
In regard thereto, diseases based on the regulation of VR-1 activity include pain, acute pain, chronic pain, neuropathatic pain, pain after operations, migraine, arthralgia, neuropathy, nerve injury, diabetic neuropathy, neuropathic disease, neurodermatitis, stroke, overactive bladder, irritable bowel syndrome, a respiratory problem such as asthma, chronic obstructive pulmonary disease, etc., stimuli of the skin, eye, and mucous membrane, pruritus, fever, gastric-duodenal ulcer, inflammatory bowel disease or inflammatory disease and urgency urinary incontinence (KR Patent Publication No. 10-2004-0034804), anti-obesity effects (Pharmacol. Rev., 1986, 38, 179), etc.
Both the VR-1 agonist and antagonist in terms of pharmaceutical mechanisms may be used to treat the diseases as mentioned above. The pharmaceutical mechanism responsible for the alleviation effect of pain by the VR1 agonist is based on desensitization of capsaicin-sensitive sensory neurons. Specifically, pain and stimulation of the sensory neuron desensitizes the nerve cell, thereby preventing pain from occurring due to other noxious stimuli. Because of the initial pain, the VR-1 agonist is limitedly developed now as a topical therapeutic agent. In contrast, the VR-1 antagonist has a mechanism that blocks the recognition of a pain signal of the sensory neuron and thus does not cause any initial pain and does not cause any stimulation, and is thereby mainly studied as a treatment intended to treat systemic disease.
Meanwhile, as a known method of preparing a benzoimidazole derivative, Korean Patent Publication No. 10-2007-0113207 discloses a variety of benzoimidazoles as the VR-1 antagonist and a method of preparing the same, wherein a benzoic acid derivative is synthesized and subjected to amidation with a diamine derivative and then to cyclization to benzoimidazole. However, this method is problematic in undesirably increasing the amount of impurities and the cost and decreasing the purity, making it difficult to apply it to production because the preparation process includes a two-step cyclization.
Therefore, the present inventors have studied conventional methods of preparing benzoimidazole derivatives and discovered that when benzaldehyde is used as an intermediate instead of a benzoic acid derivative conventionally used, the reaction may become simple, the need for an expensive reagent may be obviated, the yield may increase and the amount of impurities may decrease, thereby culminating in the present invention.